Process for the production of n1-arylsulfonyl-n2-alkyl ureas



United States Patent Ofifice 3,075,012 Patented Jan. 22, 1963 3,075,012 PROCESS FOR THE PRODUCTION OF N -ARYL- sULFONYL-N -ALKYL UREAS Karl Koehei, Neuhausen am Rheinfall, and Robert Egli, Schatfhausen, Switzerland, assignors to Cilag-Chemie Limited, Schaithausen, Switzerland, a Swiss company No Drawing. Filed Apr. 5, 1960, Ser. No. 20,034 Claims priority, application Switzerland Apr. 7, 1959 7 Claims. (Cl. 260-553) The present invention relates to a process for the production of N -arylsulfonyl-N -alkyl ureas, whereby aryl signifies a phenyl radical, a lower alkylphenyl radical, a lower alkoxyphenyl radical, a halogenophenyl radical, or a p-aminophenyl radical, and alkyl is an alkyl radical containing from 2 to 8 carbon atoms.

N -phenyl-, alkylphenyl-, -alkoxyphenyland -halogenophenyl-sulfonyl-N -alkyl ureas have been known for some time (cf. British Patents Nos. 808,073, 808,072, and 808,071, Austrian Patent No. 196,413, and Swiss Patents Nos. 331,999 to 332,007).

It is also known from these patents to produce such N -arylsulfonyl-N -alkyl ureas by reacting N-arylsulfonyl ureas with alkyl-amines (cf. Swiss Patent No. 332,005). This process is called the transamination process by the chemist skilled in the art.

Repetition of the examples of Swiss Patent No. 332,005 applied to the production of N -p-tosyl-N -n-butyl urea gives when working without diluent a yield of 2.5%, and when working with o-dichlorobenzene as diluent, which is proposed in this specification, a yield of Of course, such yields render impossible a technical application of this process. It was subsequently suggested to convert N -aryl-sulfonyl-N -acyl ureas into their salts by means of alkylamines and to heat the resulting salts to temperatures exceeding 100 C. (cf. Austrian Patent No. 195,436 and GermanPatent No. 1,043,318). Better yields can in fact be obtained with this process; it has, however, the disadvantage of requiring one step more than the simple transamination process.

' N -p-aminophenylsulfonyl- (abbreviated=N -sulfanilyl-) N -methyl-, -N -ethyl-, -N -propyland -N -butyl ureas have been known for a long time (cf. Example 1 of East German specification No. 4,769, Example 11 of Danish specification No. 70,259, and Example 11 of Norwegian specification No. 71,236).

' As a rule, compounds are used for the production of N -substituted sulfanilyl ureas which contain in the paraposition to the sulfonyl group a group which can be converted into a free amino group by hydrolysis or reduction. After completion of the formation of the sulfonyl urea grouping, this group is then converted into an amino group.

It has also been suggested to subject sulfanilyl urea to a so-called transamination using amines, adding acid in order to avoid side reactions (cf. page 1, lines 91-96 and Example 4 of East German specification No. 9,688). If this suggested process is used, i.e. if sulfanilyl urea hydrochloride is heated with butylamine hydrochloride in a mixture of dioxane and pyridine for a few hours, then a reaction mixture is obtained which is only partially soluble in dilute hydrochloric acid, so that not only does it contain the N -sulfanilyl-N -butyl urea formed but also many by-products. In Example 2 of East German speci-v fication No. 13,762 it is suggested to react sulfanilyl urea with butylamine in glacial acetic acid as solvent. The repetition of this example did not give the stated yield of 70% but only 52% of a product which was not pure. After purification of the product, the yield only amounted to 40% of the theoretical value.

It was now surprisingly found that N -arylsulfonyl-N alkyl ureas can be obtained in a very simple manner and 2 in excellent yields and with very good purity when performing the reaction of an arylsulfonyl urea with an alkylamine in a ketone of a boiling point of approximately -120 0., preferably 120 C., at a molecular ratio of sulfonyl urea to alkylamine of 1:1.2, care being taken that the ammonia which is split off is removed from the reaction mixture as quickly and as completely as poss-ible.

As already mentioned, aliphatic ketones boiling at temperatures of between 100 and C. have proved to be advantageous solvents. The possibility that the reaction promoting influence of the aliphatic ketones is in any way connected with the intermediary formation of ketimines (R: lower alkyl radicals; alkyl: an alkyl radical containing from 2 to 8 carbon atoms), cannot be excluded, but has not been proved.

It is advantageous to choose as solvent a ketone which is little or practically insoluble in water. After termination of the transamination, the resulting N -arylsulfonyl- N -alkyl urea can be brought into solution in the aqueous phase by the addition of an aqueous solution of an alkali hydroxide, While the ketone, which contains various im purities, is separated oif. Thus, an additional purification of the end product is obtained.

As ketones complying with the above requirements shall be mentioned: methyl isobutyl ketone, methyl-npropyl ketone, methyl secondary butyl ketone, diethyl ketone, ethyl isopropyl ketone, etc.

It is also possible to use a mixture of various ketones, such as for instance a higher and a lower boiling ketone, and to thus adjust the boiling point to the desired height.

The fastest possible removal of the split otf ammonia can be accomplished in various manners known to the chemist skilled in the art. Since the reaction is carried through with the ketone at boiling point,it is necessary to provide the reaction kettle with a cooling device. The gas evolution can be facilitated by choosing a suitable cooling device. The wider the aperture of the'cooling device is, the quicker does the ammonia escape.

The ammonia can also be removed at reduced pressure; Of great influence is the vigorous boiling of the ketone and the vigorous stirring of the solution. It is also possible to conduct through the reaction solution a strong flow of nitrogen or of another inert gas.

As arylsulfonyl ureas can be used: benzenesulfonyl urea, p-chlorobenzenesulfonyl urea, p-tosyl urea, p-methoxybenzenesulfonyl urea, p-chloro-m-methyl-benzene-, sulfonyl urea, m,p-dimethyl-benzene-sulfonyl urea, paminobenzesulfonyl urea, and other similarly substituted benzenesulfonyl ureas.

As alkylamines can be used: ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec. butylamine, tert.butylamine, n-amylamine, isoamylamine, sec.amylamine, n-hexylamine, 2-hexylamine, heptylamine, and octylamine.

The advantage of the process for the production of N -I sulfanilyl-N -alkyl ureas according to the present invention is obvious: it is known that sulfonyl ureas are sensitive to acids and bases. By the liberation of the. amino group, which in practice takes place by the saponification of an acylamino group, the saponification action also attacks the sulfonyl urea grouping; the yield is thus reduced and, furthermore, the end product is contaminated.

Contrary to the processes formerly used the process according to the present invention permits touse the free? p-aminophenylsulfonyl urea, and the resulting N -sulfanilyl-N -alkyl urea is obtained immediately in pure form.

a then filtered. The

a wise introduction lasts approximately The following examples are given for the purpose of illustrating the invention; they are not intended to limit the scope'thereof.

whole is then heated to boiling, whereupon evolution of NH takes place. The evolution of NH and thus the reaction are accelerated by heating as intensively as possible as well as by fractioning devices. After complete solution has been obtained, which occurs when the reacof thefreflu'x heating requires from 30 minutes to 2 hours, heatingis continued for about 10-20 minutes, followed by 'well with 1000 g. of an aqueous 4% sodium hydroxide I tion"is nearly: completed and which depending on the kind 20 quick cooling. The pale yellow reaction solutionis stirred solution, andjthe aqueous solution of the sodium salt of the-N -p-tosyl-N -n-butylurea then separated off. The ketone layeris extracted twice with 50 cc. each of water. The combined aqueous solutions are adjusted to a pH valve of 8.5-9 as quickly as possible while stirring by means-of 120 g. of 10% H 80 and then filtered with g.

. of Carboraffin-C. The carbon is washed with 150 cc. of

water. The filtrate-is then allowed to run'within 1-2 hours while stirring into a mixture of 800g. of methanol and 500, g. of H 80 Seeding is necessary after the introduction of A of the total quantity. Cooling to -20 C. is followed by adjustment to a pH value of 3-3.5 and stirring for another %-1 hour. The crystalline product washed well with water. The white product, which can "easily be filtered off by suction, is dried in an air drying loyen at 401-6090. The yield is: after A hour'refiux :heating 243g. equally 90% of the theoretical value, with ;a melting point (corn) of 127-128 C., and after 2 /2 -htjmrsof reflux heating. 230 g., equalling 85% of the theo- Ieticalyalue, with amelting p'oint.(corr.) of 126-127 C.

- issubsequentlyfiltered off with suction or centrifuged and ousstirring, whereupon evolution of ammonia takes place lasting 35 minutes. The now clear'solution is cooled to 120 C. and then' stirred with 700cc. of an aqueous 4% sodium hydroxidesolution. The, aqueous, layer is separated off and the ketone layer extracted twice with cc. each of water. The combined aqueous solutions are adjusted toa. pH valueof 8.7 by means of 10% sulfuric acid, stirredwith 4 g. of Carboraflin-C, and the whole filtrate is given dropwise while stirring into a mixture of 700 cc. of methanol and 350 g. of 10% sulfuric acid. The final pH value is 3.2, andthe drop-1 hour. The whole is now stirred-for another 15 minutes, and the. crystalline slurry then filtered off with suction. After washing with water and drying in an air drying oven are obtained 165 g., corresponding to of the theoretical value, of N -p.-' chlorobenzenesulfonyl-N -n-propyl urea, of a melting point of 12930. r

Example 3.N -p-T0syl-N -Ethyl Urea In a manner analogousto thatdescribed in the aforegoing examplesare obtained from 150 g. of N- -to.syl urea, 35 g. of ethylamine (dissolved in 200 cc. of methyl isobutyl ketone) and 1200 cc. of methyl isobutylk'etone methyl-n-propyl ketone the whole as solvent after 3 hours of boiling and the usual working up 148g. of N -p-tosyl-N -ethyl urea, equalling 87% of the theoretical value, which melts at 141-142 C.

Example 5.N -Sulfanilyl-N -n-Butyl Urea 215 g. of sulfanilyl urea are suspended in 960 g. (1200 cc.) of methyl isobutyl ketone and 87.7 g. (1.2 mol) of butylamine allowed to run in with stirring within the course of 15-30 minutes. A thick but stirrable slurry results, together with a rise in temperature of about 10 C. In order to complete the salt formation, stirring is continued for about a half hour and the reaction mixture then heated quickly to boiling point, whereupon evolution of ammonia takes place. The evolution of armnonia and thusthe reaction are accelerated by boiling as intensively as possible as well as by fractioning devices. After complete solution has been obtained, which occurs when the reaction is almost completed, boiling is continued for about 10-15 minutes and the reaction mixture is then poured with intensive stirring into 1000 g. of aqueous 4% sodium hydroxide solution. The temperature thereby rises to about 40 C. After stirring well, the pale yellow so dium salt solution is separated off. The methyl isobutyl ketone layer is then extracted twice with 100 cc. each of Water. The combined aqueous solutions are adjusted to a pHvalue of 8.5 with about 90 g. of 10% acetic acid, stirred with 1.0 g. of Carboraffin-C, filtered andwashed with 700 cc. of water. The solution is diluted with a further 700 cc. of water, heated to 40-50 C., and the desired product is precipitated out, at first quite slowly with stirring and seeding, within about one hour with about 600g; of 10% acetic acid to a pH of 6.0 to 6.5. After a few minutes, the 40-50 C. warm slurry, which consists of voluminous small crystalline needles, is filtered off with suction: or centrifuged and washed well with water. Drying is carried out in an air drying oven at 40- 6.0 C. Theyield amounts to 244 g., i.e. 90% of the theoretical value.

Example 6.-N -Sulfanilyl-N -n-Butyl Urea 807 g. of sulfanilyl urea are suspended in 2000 cc. of methyl-nrpropyl ketone, and a solution of 329 g. of nbutylamine in 2000 cc. of methyl n-propyl ketone permitted'to'flowinto this suspension. There results a thick but still stirrable slurry. The temperature rises automatically to 37 C. After adding a further 500 cc. of is heated. to boiling while stirring, which causes a strong evolution of ammonia. After 45-50 minutes the reaction is terminated and everything dissolvedclearly. There follows cooling and then stirring with 3750 cc. of aqueous 1 N NaOH. The aqueous alkaline solution is separated-off and the ketone layer, extractedonce morewith 700cc. of water. The combined aqueous solutionsv are adjusted to a pH value of 8.5, stirred with 40 g. of Carboraffin-C and then filtered. Acetic acid (2 N to 4 N- dilutions are usable) in a fine jet is allowed'to flow into the filtrate while stirring. This is followed by adjustment to a pH value of 6-6.5 and stirring for a further 15-30 minutes. The crystalline productis filtered off with suction, washed well with water and dried in an air drying oven. There result 925 g. of pure N -sulfanilyl-N -n-butyl urea. The yield corresponds to 91% of the theoretical value.

In the same manner can be reacted: patosyl urea with ethylamine, n-propyl amine, isopropylamine, amylamine, isoamylamine, heptylamine, octylamine. It is also possible to use for the reaction p-methoxybenzenesulfonyl urea, p-

isopropylbenzenesulfonyl urea, p fluorobenzenesulfonyl urea instead of p-tosyl urea.

What we claim is:

1. In an N -arylsulfonyl-N -alkyl urea forming reaction conducted in a solvent consisting essentially of an N- monocyclic-arylsulfonyl urea, wherein the aryl moiety is a member selected from the class consisting of phenyl, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl and p-aminophenyl, and an alkylamine of from 2 to 8 carbon atoms, the improvement which comprises carrying out the reaction between said N-monocyclicarylsulfonyl urea and alkylamine in a ratio of 1: 1.2 moles respectively in boiling ketone having a boiling point in the range of between 100 C. and 120 (3., and removing the ammonia being split off as quickly as possible.

2. The method according to claim 1 wherein the ketone is substantially insoluble in water.

3. The method according to claim 1 wherein N-arylsulrfonyl urea is p-toluenesul-fonyl urea.

4. The method according to claim 1 wherein N-arylsulfonyl urea is N-p-chlorobenzenesnlfonyl urea.

5. The method according to claim -1 wherein N-arylsulfonyl urea is snlfonilyl urea.

6. The method according to claim 1 wherein the is methyl-n-propylketone.

7. The method according to claim 1 wherein the ketone is methylisobutylketone.

ketone References Cited in the file of this patent FOREIGN PATENTS 604,259 Great Britain June 30, 1948 332,005 Switzerland Sept. 30, 1958 70,259 Denmark Nov. 28, 1949 OTHER REFERENCES Bergmann: The Chemistry of Acetylene and Related Compounds, page '80 (1948). 

